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2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

Legoabe LJ, Petzer A, Petzer JP - Drug Des Devel Ther (2015)

Bottom Line: Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform.Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform.Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.

ABSTRACT
Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus

Reversibility of the inhibition of MAO-B by 2e.Notes: MAO-B was preincubated in the absence of inhibitor (NI – dialyzed), in the presence of 2e (2e – dialyzed) and in the presence of the irreversible inhibitor, (R)-deprenyl (depr – dialyzed). These mixtures were subsequently dialyzed for 24 hours and the residual enzyme activity was measured. For comparison, the residual activity of undialyzed mixtures of MAO-B with 2e is also shown (2e – undialyzed).Abbreviations: MAO, monoamine oxidase; h, hour.
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f2-dddt-9-3635: Reversibility of the inhibition of MAO-B by 2e.Notes: MAO-B was preincubated in the absence of inhibitor (NI – dialyzed), in the presence of 2e (2e – dialyzed) and in the presence of the irreversible inhibitor, (R)-deprenyl (depr – dialyzed). These mixtures were subsequently dialyzed for 24 hours and the residual enzyme activity was measured. For comparison, the residual activity of undialyzed mixtures of MAO-B with 2e is also shown (2e – undialyzed).Abbreviations: MAO, monoamine oxidase; h, hour.

Mentions: Employing dialysis, the present study also investigated the reversibility of MAO-B inhibition by one representative inhibitor, compound 2e (IC50 =0.003 µM). The reversibility of inhibition was examined by measuring the recovery of enzyme activity after dialysis of enzyme-inhibitor mixtures.26 Since none of the 2-acetylphenol analogs were potent MAO-A inhibitors, only the reversibility of MAO-B inhibition was further investigated. MAO-B and 2e, at an inhibitor concentration of 4× IC50, was incubated for 15 minutes, dialyzed for 24 hours, and the residual enzyme activity was subsequently measured. The results are given in Figure 2, which show that the MAO-B inhibition by 2e is only partially reversed after 24 hours of dialysis, with the catalytic activity recovering to 52% of the negative control value (activity in the absence of inhibitor). For reversible inhibition, the enzyme activity is, however, expected to recover to 100% after dialysis. The enzyme activity of undialyzed mixtures of MAO-B and 2e is 30% of the control value. As positive control, the irreversible inhibitor, (R)-deprenyl, was similarly incubated with MAO-B and dialyzed. As expected for irreversible inhibition, enzyme activity is not recovered, with only 1.6% activity remaining. While the molecular basis for the observation that MAO-B inhibition is only partially reversed by dialysis, is not known, high potency MAO-B inhibitors such as 2e may act by tight binding. Potential tight binding of inhibitors to MAO-B has been reported on a number of occasions,30–33 and partial recovery of MAO-B activity following dialysis of enzyme-inhibitor mixtures has previously been reported.25 Further investigation is necessary to clarify this point.


2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

Legoabe LJ, Petzer A, Petzer JP - Drug Des Devel Ther (2015)

Reversibility of the inhibition of MAO-B by 2e.Notes: MAO-B was preincubated in the absence of inhibitor (NI – dialyzed), in the presence of 2e (2e – dialyzed) and in the presence of the irreversible inhibitor, (R)-deprenyl (depr – dialyzed). These mixtures were subsequently dialyzed for 24 hours and the residual enzyme activity was measured. For comparison, the residual activity of undialyzed mixtures of MAO-B with 2e is also shown (2e – undialyzed).Abbreviations: MAO, monoamine oxidase; h, hour.
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Related In: Results  -  Collection

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Show All Figures
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f2-dddt-9-3635: Reversibility of the inhibition of MAO-B by 2e.Notes: MAO-B was preincubated in the absence of inhibitor (NI – dialyzed), in the presence of 2e (2e – dialyzed) and in the presence of the irreversible inhibitor, (R)-deprenyl (depr – dialyzed). These mixtures were subsequently dialyzed for 24 hours and the residual enzyme activity was measured. For comparison, the residual activity of undialyzed mixtures of MAO-B with 2e is also shown (2e – undialyzed).Abbreviations: MAO, monoamine oxidase; h, hour.
Mentions: Employing dialysis, the present study also investigated the reversibility of MAO-B inhibition by one representative inhibitor, compound 2e (IC50 =0.003 µM). The reversibility of inhibition was examined by measuring the recovery of enzyme activity after dialysis of enzyme-inhibitor mixtures.26 Since none of the 2-acetylphenol analogs were potent MAO-A inhibitors, only the reversibility of MAO-B inhibition was further investigated. MAO-B and 2e, at an inhibitor concentration of 4× IC50, was incubated for 15 minutes, dialyzed for 24 hours, and the residual enzyme activity was subsequently measured. The results are given in Figure 2, which show that the MAO-B inhibition by 2e is only partially reversed after 24 hours of dialysis, with the catalytic activity recovering to 52% of the negative control value (activity in the absence of inhibitor). For reversible inhibition, the enzyme activity is, however, expected to recover to 100% after dialysis. The enzyme activity of undialyzed mixtures of MAO-B and 2e is 30% of the control value. As positive control, the irreversible inhibitor, (R)-deprenyl, was similarly incubated with MAO-B and dialyzed. As expected for irreversible inhibition, enzyme activity is not recovered, with only 1.6% activity remaining. While the molecular basis for the observation that MAO-B inhibition is only partially reversed by dialysis, is not known, high potency MAO-B inhibitors such as 2e may act by tight binding. Potential tight binding of inhibitors to MAO-B has been reported on a number of occasions,30–33 and partial recovery of MAO-B activity following dialysis of enzyme-inhibitor mixtures has previously been reported.25 Further investigation is necessary to clarify this point.

Bottom Line: Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform.Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform.Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.

ABSTRACT
Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus